Dr. Reilly has a track record in mechanistic patient oriented research (POR) and mentorship at the University of Pennsylvania (Penn). His Cardiometabolic Research Program is dedicated to human translational and genomic studies of cardiometabolic diseases (CMD). His program is based in Penn's Cardiovascular (CVI) and Translational (ITMAT) Institutes and is highly integrated into the training missions sponsored by Penn's Clinical and Translational Science Award (CTSA). This provides an outstanding environment for translational POR and for mentoring K24 trainees. He has had a track record of continuous NIH funding, mentorship of multiple physician scientists in translational POR, and numerous high-impact publications led by multiple K24 trainees, several of whom have established their own independent POR careers. Dr Reilly is committed to training young clinical investigators in cutting-edge translational technologies and mentoring them to independent careers in POR. With current K24 support, he has been successful in mentoring a new generation of POR researchers (thirty K24 trainees) and in expanding his own POR in CMD (PI for 3 R01, one U01). In this K24 renewal, he proposes to (1) augment his scientific and mentoring skills and devote more time to mechanistic POR, (2) focus on mentoring new clinical investigators in mechanistic POR, and (3) pursue innovative POR in a unique training environment for mentoring young clinical investigators to independent careers in POR. Macrophages represent a critical cell type at the intersection of many CMDs. Reilly's group has developed a method for differentiating human induced pluripotent stem cells (hiPSC) to macrophages (IPS-DM), a powerful system for macrophages functional genomics. Current K24 work shows that (a) IPS-DM are phenotypically and transcriptionally similar to their primary counterparts, (b) IPS-DM can be activated to functionally distinct M1 and M2 phenotypes, and (c) IPS-DM from Tangier disease patients reproduce disease specific macrophage phenotypes. Although recent genomic discoveries have identified multiple novel loci for CMD, the key challenge remains in defining the role of specific cell types, including macrophages, in causing disease. Alternative splicing (AS) plays a critical role in tissue and cell-specific functins but its role in macrophage phenotypes is also unknown. In preliminary studies, the Reilly group performed (a) CRISPR/Cas gene-editing in hiPSC of a LIPA, a novel loci for CAD, to study (in Aim 1) macrophage-specific functions of LIPA GWAS CAD risk alleles and (b) genome-wide RNA-seq analysis of splicing factors (SFs) in macrophages to explore (in Aim 2) a role for specific SFs (CELF1 and RBM43) and alternative splicing (AS) in macrophage- specific functions and human disease. Dr. Reilly will dedicate 25% effort to this K24 proposal (5% to augment his mentorship and POR skills; 5% to the research proposal; and 15% to mentoring). The K24 renewal will allow him to expand his mechanistic POR program while simultaneously dedicating experienced effort to train young clinical investigators.